This invention is directed to minimization of a carbon footprint created during the operation of a lyophilization system used in the pharmaceutical industry, or in the food industry, by i) reducing the use of chlorofluorocarbons, and ii) significantly reducing the use of rotating equipment and the consequent use of electricity.
Biologically active products including pharmaceuticals such as vitamins, hormones, tranquilizers and antibiotics; proteins such as enzymes and gelatins; and control products such as plasma or serum are in wide spread use. Despite this fact, there are still many problems with the way in which they are produced and the form in which they are provided. For example, since they are biologically active, they should be provided in a form which will preserve their biological activity for a reasonable time. One method of doing this is to freeze the substance and retain it in its frozen state. However, this entails extra handling and equipment necessary to keep the substance frozen at all times.
Alternatively, quantities of a substance are frozen in bulk form and subsequently lyophilized. By doing so, the product no longer has to be maintained at temperatures below freezing, but the slow freezing that takes place during bulk freezing creates other problems. For example, slow freezing promotes the development of concentration gradients. Thus, when blood serum or plasma is frozen slowly, cholesterol and triglyceride globules within the serum or plasma are forced to coalesce. These globules, upon dissolution of the lyophilized product in an aqueous solvent, apparently do not re-disperse but remain coalesced, resulting in a non-uniform product.
Another problem is that slow freezing produces degradation of various biological constituents. Freezing of enzyme solutions, for example, generally appears to have a degrading effect on the enzymes. The slow freezing that takes place during bulk freezing and the concentration gradients that build up during this process, increase the degradation which occurs.
One effort to counteract enzyme degradation resulting from slow freezing of a plasma, for example, has been to entirely remove the enzyme and other constituents from the plasma, and add (weigh) in predetermined quantities of these substances so to achieve a constant level of these constituents after the product is frozen and dried. The weight of an enzyme, however, does not truly represent the amount of material that needs to be added. Because enzymes are subject to degradation, the “true” measure of enzyme concentration is activity, for which weight is not an accurate substitution.
Finally, the reconstitution of lyophilized substances by dissolution in water encounters difficulties when the substance is frozen in bulk form. A reconstitution may require from 20-30 minutes and often results in a lack of clarity. This is a particularly bothersome problem with control products, such as serum or plasma, when subsequent photometric analysis is performed on them. Furthermore, when products are frozen in bulk form they are difficult to dispense in any other form but their reconstituted form.
Sometimes fluorocarbon refrigerants may have a higher boiling point than other liquid refrigerants, for example, liquid nitrogen. A higher boiling point, being closer to the temperature of the solution droplets, results in less of a vapor phase barrier between the particle and the refrigerant. This can result in more rapid freezing of the particles than can be achieved with even colder refrigerants such as liquid nitrogen.
Fast freezing also prevents the loss of those constituents of a solution that would otherwise be soluble in a fluorocarbon. Thus, when the product is serum or plasma, for example, negligible loss of cholesterol and triglycerides has been found, even though these are organic compounds soluble in some fluorocarbons. Specifically, with a lower detection limit of 2 to 3 percent (2-3%), no loss of these substances has been found. It will also be noted that the use of liquid nitrogen may sometimes produce less spherical and less uniform sized particles.
Currently, a lyophilization or lyo operation involves placing a product in a lyophilization chamber which is then cooled down until the product is frozen. During the next step of the process, hot oil is used to heat shelves within the chamber on which the product is placed so to sublimate water crystals formed on the product as it freezes.
This operation has a number of drawbacks. First, the entire chamber must be cooled down. Second, the hot oil may leak in the chamber causing both product contamination and clean-up problems. Third, if mechanical refrigeration is used, its maintenance is expensive. Fourth, it is an expensive process particularly for low cost products.
In addition to the above, pharmaceutical, biotechnical and food industries are now attempting to reduce their carbon footprints; and, due to an increased demand for more flexibility in performance because of the aqueous and non-aqueous media in the products they make, only limited alternatives are available. Economic factors and operating expenses are both critical factors in any option being considered.
Liquid nitrogen (LIN) based lyophilization or lyo systems are among the options under consideration, and it is believed that installation of a LIN system is more expensive per kilowatt-hour (kwh) cooling output than the electrical energy needed to produce the same cooling effect in a compressor based system. However, it has been shown that, unlike compressor based refrigeration systems, operating costs of a LIN system are lower such that LIN based systems are more economical over the long run than cooling with compressors.